Note: Descriptions are shown in the official language in which they were submitted.
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
DESCRIPTION
TITLE OF INVENTION
USE OF ERIBULIN AND LENVATINIB AS COMBINATION THERAPY FOR
TREATMENT OF CANCER
TECHNICAL FIELD
The invention provides methods and compositions for use in treating diseases
associated
with excessive cellular proliferation, such as cancer.
BACKGROUND ART
Cancer is a term used to describe a wide variety of diseases that are each
characterized
by the uncontrolled, malignant growth of a particular type of cell. It begins
in a tissue containing
such a cell and, if the cancer has not spread to any additional tissues at the
time of diagnosis,
may be treated by, for example, surgery, radiation, or another type of
localized therapy. However,
when there is evidence that cancer has metastasized from its tissue of origin,
different
approaches to treatment are typically used. Indeed, because it is not possible
to determine the
extent of metastasis, systemic approaches to therapy are usually undertaken
when any evidence
of spread is detected. These approaches involve the administration of, for
example,
chemotherapeutic drugs that interfere with the growth of rapidly dividing
cells, such as cancer
cells.
Halichondrin B is a structurally complex, macrocyclic compound that was
originally
isolated from the marine sponge Halichondria okadai, and subsequently was
found in Axinella sp.,
Phakellia carteri, and Lissodendoryx sp. A total synthesis of halichondrin B
was published in
1992 (Aicher et al., J. Am. Chem. Soc. 114:3162-3164, 1992). Halichondrin B
has been shown to
inhibit tubulin polymerization, microtubule assembly, betas-tubulin
crosslinking, GTP and
vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis in vitro.
This molecule has
also been shown to have anti-cancer properties in vitro and in vivo.
Halichondrin B analogs
having anti-cancer activities are described in U.S. Patent No. 6,214,865 B1.
Eribulin is a synthetic analog of halichondrin B. Eribulin is also known as ER-
086526,
and has been assigned CAS number 253128-41-5 and US NCI designation number NSC-
707389.
The mesylate salt of eribulin (eribulin mesylate, which is marketed under the
trade name
HALAVEN and is also known as E7389) is approved for the treatment of patients
with breast
cancer who have previously received at least two chemotherapeutic regimens for
the treatment of
metastatic disease that should have included an anthracycline and a taxane in
either the adjuvant
or metastatic setting.
1
CA 02915005 2015-12-10
WO 2014/208774 PCT/JP2014/067723
The chemical name for eribulin mesylate is
(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-
[(2S)-3-
amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-
11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-
Rfuro[2',3.:5,6]pyrano[4,3-
b][1,4]dioxacyclopentacosin-5(41-1)-one, methanesulfonate (salt), and it can
be depicted as:
H2 N HO 0/
H
E7080 (also known as lenvatinib mesylate) is an active inhibitor of multiple
receptor
tyrosine kinases (e.g., receptor tyrosine kinases involved in angiogenesis and
tumor proliferation)
,
including vascular endothelial growth factor (VEGF), fibroblast growth factor
(FGF), platelet-
derived growth factor receptor a (PDGFRa), KIT, and RET proto-oncogene
receptors. It has
been assigned CAS number 857890-39-2 (also see 417716-92-8). The chemical name
for
lenvatinib mesylate is 4-[3-chloro-4-
[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-6-
quinolinecarboxannide, methanesulfonate (1:1). [It is also named as 443-chloro-
4-(N'-
cyclopropylureido)phenoxyl]-7-methoxyquinoline-6-carboxamide, and N-{4-[(6-
carbamoy1-7-
methoxyquinolin-4-yl)oxy]-2-chlorophenyI}-N'-cyclopropylurea
monomethanesulfonate.]
Lenvatinib mesylate can be depicted as:
I
H2N
T
o o ,..... = I-1,3C ¨ SO3H
I Fit, Ar,
N N
H H
CI .
SUMMARY OF INVENTION
The invention is based on the observation that the combination of eribulin and
lenvatinib
shows improved (e.g., synergistic) antitumor effects. Therefore, the present
invention features
the co-administration of eribulin (or a pharmaceutically acceptable salt
thereof, e.g., eribulin
2
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
mesylate) and lenvatinib (or a pharmaceutically acceptable salt thereof, e.g.,
lenvatinib mesylate)
in cancer treatment regimens, as well as the use of these agents for such
treatment.
The invention thus provides methods for treating a subject (e.g., a human
patient) having
or at risk of developing cancer. The methods involve administering to a
subject (i) eribulin or a
pharmaceutically acceptable salt thereof (e.g., eribulin mesylate), and (ii)
lenvatinib or a
pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate). The
invention also provides
the use of these agents for the treatment of such a subject, as well as the
use of these agents for
the preparation of medicaments for the treatment of such a subject, as
described herein. All
descriptions of methods herein are applicable in the context of such uses.
The subject may be diagnosed with cancer, in treatment for cancer, or in post-
therapy
recovery from cancer. Further, the cancer may be a primary tumor, a
metastasis, and/or a solid
tumor. In various examples, the cancer can be selected from the group
consisting of breast
cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer,
colorectal cancer, ovarian
cancer, endometrial cancer, skin cancer (e.g., melanoma), prostate cancer,
brain cancer, head
and neck cancer, liver cancer, kidney cancer, bladder cancer, gastric cancer,
gastrointestinal
cancer, cancer of the blood (e.g., leukemia), cancer of the lymphatic system,
thyroid cancer, bone
cancer (e.g., osteosarcoma), and fibrosarcoma.
The eribulin or pharmaceutically acceptable salt thereof (e.g., eribulin
mesylate) can be
administered by intravenous infusion, for example, for about 1 to about 20
minutes, or for about 2
to about 5 minutes. Further, the eribulin or pharmaceutically acceptable salt
thereof (e.g., eribulin
mesylate) can be administered in an amount in the range of about 0.1 mg/nn2 to
about 20 mg/m2,
or about 1.4 mg/m2 or 1.1 mg/m2. In addition, the eribulin or pharmaceutically
acceptable salt
thereof (e.g., eribulin mesylate) can be administered once on each of days 1
and Sofa 21-day
cycle.
The lenvatinib or pharmaceutically acceptable salt thereof (e.g., lenvatinib
mesylate) can
be administered orally, for example, in an amount in the range of about 0.1 mg
to about 100 mg,
or about 4 mg to about 24 mg. Further, in various examples, the lenvatinib or
pharmaceutically
acceptable salt thereof (e.g., lenvatinib mesylate) can be administered daily.
The eribulin or pharmaceutically acceptable salt thereof (e.g., eribulin
mesylate), and the
lenvatinib or pharmaceutically acceptable salt thereof (e.g., lenvatinib
mesylate) can be
administered substantially simultaneously or sequentially.
Treatment according to the methods of the invention can: (i) reduce the number
of cancer
cells; (ii) reduce tumor volume; (iii) increase tumor regression rate; (iv)
reduce or slow cancer cell
infiltration into peripheral organs; (v) reduce or slow tumor metastasis; (vi)
reduce or inhibit tumor
growth; (vii) prevent or delay occurrence and/or recurrence of the cancer
and/or extend disease-
or tumor-free survival time; (viii) increase overall survival time; (ix)
reduce the frequency of
treatment; and/or (x) relieve one or more of symptoms associated with the
cancer.
3
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
The invention also includes methods for decreasing the size of a tumor in a
subject.
These methods involve administering to a subject (i) eribulin or a
pharmaceutically acceptable
salt thereof (e.g., eribulin mesylate), and (ii) lenvatinib or a
pharmaceutically acceptable salt
thereof (e.g., lenvatinib mesylate). In addition, the invention includes the
use of these agents for
decreasing the size of a tumor in a subject, as described herein.
Further, the invention includes kits for use in treating cancer, decreasing
tumor size, or
inducing or increasing an immune response to a tumor in a subject. The kits
include (i) eribulin or
a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate), and (ii)
lenvatinib or a
pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate).
Optionally, these agents are
present in dosage form.
Other features of the invention will be apparent from the following detailed
description,
the drawings, and the claims.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is a graph showing the antitumor effects of E7389 in combination with
E7080 in
an A375 human malignant melanoma xenograft model in mice. Data represent the
mean SEM
(n=6). Arrows on 17 and 24 days after transplantation show starting day of
treatments, the arrow
represents E7389, and the line represents E7080. i.v. = intravenous, p.o. =
per os, 01Dx14 =
once daily for 14 days, Q7Dx2 = once a week for 2 weeks. *P < 0.05 versus
E7389 3.0 mg/kg
single agent on day 30 (one-way analysis of variance followed by the Dunnett's
multiple
comparison test).
Figure 2 is a graph showing relative body weight change of animals treated
with E7389
alone, E7080 alone, and E7389 + E7080 in combination. Data represent the mean
SEM (n=6),
Arrows on 17 and 24 days after transplantation show starting day of
treatments, the arrow
represents E7389, and the line represents E7080. i.v. = intravenous, p.o. =
per os, Q1Dx14 =
once daily for 14 days, Q7Dx2 = once a week for 2 weeks. Body weight loss was
observed after
E7389 administered alone at 3.0 mg/kg and in the combination treatment groups.
Partial
recovery from body weight loss was observed in all mice upon completion of
drug treatment.
Figure 3 is a graph showing the antitumor effects of E7389 in combination with
E7080 in
NCI-H1993 (left) or PC-9 (right) human non-small cell lung cancer xenografts
in mice. Data
represent the mean SD (n=5). The arrows on Day 0 and Day 7 show injection of
E7389, and
the line from Day 0 to Day 11 show treatment of E7080. i.v. = intravenous,
p.o. = per os, Q1Dx12
= once daily for 12 days, Q7Dx2 = once a week for 2 weeks. *P < 0.05:
statically analysis of
combination group vs. each single therapy group (repeated measured ANOVA
test).
DESCRIPTION OF EMBODIMENTS
The invention provides methods for treating cancer involving administration of
eribulin
and lenvatinib (or pharmaceutically acceptable salts thereof, e.g., mesylate
salt), as well as the
4
use of these agents for cancer treatment or the preparation of medicaments
therefor. As shown
in the Examples section, below, eribulin mesylate and lenvatinib mesylate,
when used in
combination, potentiate the anti-cancer effects of one another. In one
example, the combination
therapy results in tumor regression. Accordingly, treatment of cancer by
administering eribulin
and lenvatinib (or pharmaceutically acceptable salts thereof, e.g., mesylate
salt), according to the
methods of the invention, can (i) reduce the number of cancer cells; (ii)
reduce tumor volume; (iii)
increase tumor regression rate; (iv) reduce or slow cancer cell infiltration
into peripheral organs;
(v) reduce or slow tumor metastasis; (vi) reduce or inhibit tumor growth;
(vii) prevent or delay
occurrence and/or recurrence of the cancer and/or extend disease or tumor-free
survival time;
(viii) increase overall survival time; (ix) reduce the frequency of treatment;
and/or (x) relieve one
or more of symptoms associated with cancer.
Pharmaceutical Compositions, Dosage, and Methods
Methods for the synthesis of eribulin (and pharmaceutically acceptable salts
thereof, such
as eribulin mesylate) are described, for example, in U.S. Patent No.
6,214,865; U.S. Patent No,
7,982,060; U.S. Patent No. 8,350,067; and U.S. Patent No. 8,093,410.
Vlethods relating to lenvatinib (and pharmaceutically
acceptable salts thereof, such as lenvatinib mesylate) and its synthesis are
described, for
example, in U.S. Patent No. 7,612,092.
As noted above, eribulin and/or lenvatinib can optionally be used in the
present invention
in a salt form. There are no particular limitations as to the salt used,
whether inorganic acid salt
or organic acid salt. For example, the salt may be selected from
methansulfonic acid salt (e.g.,
eribulin mesylate or lenvatinib mesylate), hydrochloric acid salt, sulfuric
acid salt, citric acid salt,
hydrobromic acid salt, hydroiodine acid salt, nitric acid salt, bisulfate,
phosphoric acid salt, super
phosphoric acid salt, isonicotinic acid salt, acetic acid salt, lactic acid
salt, salicic acid salt, tartaric
acid salt, pantotenic acid salt, ascorbic acid salt, succinic acid salt,
maleic acid salt, fumaric acid
salt, gluconic acid salt, saccharinic acid salt, formic acid salt, benzoic
acid salt, glutaminic acid
salt, ethanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic
acid salt, pamoic acid
salt (pamoate), and so on.
Pharmaceutical compositions including eribulin or lenvatinib (or
pharmaceutically
acceptable salts thereof, such as mesylate salt) can be prepared using
standard methods known
in the art (see, e.g., the patents noted above). Pharmaceutical compositions
used in the
invention can be prepared by, for example, mixing or dissolving the active
ingredient(s), having
the desired degree of purity, in a physiologically acceptable diluent,
carrier, excipient, or stabilizer
(see, e.g., Remington's Pharmaceutical Sciences (20th edition), ed. A.
Gennaro, 2000, Lippincott,
Williams & Wilkins, Philadelphia, PA). Acceptable diluents include water and
saline, optionally
including buffers such as phosphate, citrate, or other organic acids;
antioxidants including
Date Recue/Date Received 2020-10-09
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid;
low molecular
weight (less than about 10 residues) polypeptides; proteins, such as serum
albumin, gelatin or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino
acids such as glycine,
glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or
other
carbohydrates including glucose, mannose, or dextrins; chelating agents such
as EDTA; sugar
alcohols such as mannitol or sorbitol; salt-forming counterions such as
sodium; and/or nonionic
surfactants such as TWEENT", PLURONICSTM, or PEG.
Optionally, the formulations of the invention contain a pharmaceutically
acceptable
preservative. In some embodiments the preservative concentration ranges from
0.1 to 2.0%,
typically v/v. Suitable preservatives include those known in the
pharmaceutical arts, such as
benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben. Further,
the eribulin and/or
lenvatinib (or pharmaceutically acceptable salts thereof, such as mesylate
salts) formulations
optionally include a pharmaceutically acceptable salt, such as sodium chloride
at, for example,
about physiological concentrations. Thus, in one example, eribulin (or a
pharmaceutically
acceptable salt thereof, such as eribulin mesylate) is formulated in 0.9%
Sodium Chloride
Injection (USP). In another example, lenvatinib (or a pharmaceutically
acceptable salt thereof,
such as lenvatinib mesylate) is formulated for oral administration, e.g., in
liquid, tablet, or capsule
form.
In some examples, the formulations noted above (and others) can be used for
parenteral
administration of the drugs. Thus, the drugs can be administered by routes
including intravenous,
intra-tumoral, peri-tumoral, intra-arterial, intra-dermal, intra-vesical,
ophthalmic, intramuscular,
intradermal, intraperitoneal, pulmonary, subcutaneous, and transcutaneous
routes. Other routes
can also be used including, for example, transmucosal, transdermal,
inhalation, intravaginal,
rectal, and oral administration routes.
The dosage of the eribulin and/or lenvatinib (or pharmaceutically acceptable
salts thereof,
such as mesylate salt) administered may differ markedly depending on the type
of target disease,
the choice of delivery method, as well as the age, sex, and weight of the
patient, the severity of
the symptoms, along with other factors, as can be assessed by those of skill
in the art. The drugs
are administered using amounts and regimens that obtain the desired effect
(e.g., tumor
regression; see also, e.g., the list of effects (i)-(x) set forth above). The
amounts may have
additive or synergistic effects on one or more features of cancer treatment
(e.g., tumor
regression), as is known in the art.
The drugs can be administered to a patient substantially simultaneously or
sequentially
and in either order (e.g., administration of eribulin (or a pharmaceutically
acceptable salt thereof,
such as eribulin mesylate) prior to lenvatinib (or a pharmaceutically
acceptable salt thereof, such
as lenvatinib mesylate), or vice versa). Many regimens used to administer
chemotherapeutic
drugs involve, for example, administration of a drug (or drugs) followed by
repetition of this
6
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
treatment after a period (e.g., 1-4 weeks) during which the patient recovers
from any adverse side
effects of the treatment. Typically, the number of cycles of eribulin (or a
pharmaceutically
acceptable salt thereof, such as eribulin mesylate) and/or lenvatinib (or a
pharmaceutically
acceptable salt thereof, such as lenvatinib mesylate) administration are 4-8,
e.g., 4-7, or 6. It may
be desirable to use both drugs at each administration or, alternatively, to
have some (or all) of the
treatments include only one of the drugs.
Thus, for example, the daily dosage of eribulin (or a pharmaceutically
acceptable salt
thereof, such as eribulin mesylate) may be in the range of, e.g., 0.001 mg/m2
to about 100 mg/m2
(e.g., in the range of about 0.01 mg/m2 to about 50 mg/m2, 0.1 to about 5
mg/m2, or in the range
of about 0.7 mg/m2 to about 1.5 mg/m2, or in any single amount within these
ranges (e.g., 1.4 or
1.1 mg/m2)). The drug may be administered as a single dose once a day, week,
month, or year,
or more than one dose of the drug may be administered per day, week, month, or
year. For
example, in one administration protocol, the drug may be administered once
daily on days 1 and
8 of a 21-day cycle. In another example, the drug may be administered once
daily on days 1, 8,
and 15 of a 28-day cycle. The drug can be administered over the course of,
e.g., 1 minute to 1
hour (or longer), e.g., over 2 to 5 minutes.
More specifically, in one example, a recommended dose of eribulin mesylate is
1.4
mg/m2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21-
day cycle. A
recommended dose of eribulin mesylate in patients with mild hepatic impairment
(Child-Pugh A)
is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on days 1 and 8 of
a 21-day cycle,
while a recommended dose of eribulin mesylate in patients with moderate
hepatic impairment
(Child-Pugh B) is 0.7 mg/m2 administered intravenously over 2 to 5 minutes on
days 1 and 8 of a
21-day cycle. Further, a recommended dose of eribulin mesylate in patients
with moderate renal
impairment (creatinine clearance of 30-50 mUmin) is 1.1 mg/m2 administered
intravenously over
2 to 5 minutes on days 1 and 8 of a 21-day cycle. In another example, 1.1
mg/m2 eribulin
mesylate is administered intravenously over 2 to 5 minutes on days 1, 8, and
15 of a 28-day cycle.
The daily dosage of lenvatinib (or a pharmaceutically acceptable salt thereof,
such as
lenvatinib mesylate) for adults is not particularly restricted, although the
drug may be
administered in the range of, e.g., about 0.1 mg to about 100 mg, e.g., about
4 mg to about 24
mg, or in any single amount within this range (e.g., 15 mg). The drug may be
administered as a
single dose once a day, week, month, or year, or more than one dose of the
drug may be
administered per day, week, month, or year. For example, in one administration
protocol, the
drug may be administered once daily on days 1 and 8 of a 21-day cycle. In
other embodiments,
the drug may be administered once daily on days 1, 8, and 15 of a 28-day
cycle, or on days 1, 8,
15, and 22 of a 35 day cycle. Alternatively, the drug may be administered once
daily throughout
the course of a cycle of administration of eribulin (or a pharmaceutically
acceptable salt thereof,
such as eribulin mesylate) and then, optionally, administered daily throughout
the course of one
7
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
or more additional cycles of eribulin (or a pharmaceutically acceptable salt
thereof, such as
eribulin mesylate) administration. Further, lenvatinib (or a pharmaceutically
acceptable salt
thereof, such as lenvatinib mesylate) may be administered periodically (e.g.,
daily, weekly, or
twice weekly) following the completion of one or more cycles of eribulin (or a
pharmaceutically
acceptable salt thereof, such as eribulin mesylate) treatment, optionally, for
several additional
weeks, months, or years (e.g., indefinitely).
The dosing regimens noted above for eribulin and lenvatinib (or
pharmaceutically
acceptable salts thereof, such as mesylate salt) typically start on the same
"day 1" and different
regimens (e.g., any one of those noted above) for the two drugs can be used
together. Thus, for
example, both drugs may be administered on days 1 and 8 of a 21-day cycle,
both drugs may be
administered on days 1, 8, and 15 of a 28-day cycle, etc. Alternatively, one
drug (e.g., eribulin, or
a pharmaceutically acceptable salt thereof, such as eribulin mesylate) may be
administered on
days 1 and 8 of a 21-day cycle, while the other drug (e.g., lenvatinib, or a
pharmaceutically
acceptable salt thereof, such as lenvatinib mesylate) may be administered on
days 1, 8, and 15 of
a 28-day cycle. In a further option, eribulin (or a pharmaceutically
acceptable salt thereof, such
as eribulin mesylate) is administered intravenously over 2 to 5 minutes on
days 1 and 8 of a 21-
day cycle, while lenvatinib (or a pharmaceutically acceptable salt thereof,
such as lenvatinib
mesylate) is administered once daily starting on the same day as eribulin, or
a pharmaceutically
acceptable salt thereof (e.g., eribulin mesylate) at 4-24 mg.
In addition to eribulin and lenvatinib (or pharmaceutically acceptable salts
thereof, such
as mesylate salt), the methods of the present invention may also include the
administration of one
or more additional therapeutic agents. Among these agents, immunomodulatory
agents (e.g.,
antibodies or vaccines), chemotherapeutic/antitumor agents, antibacterial
agents, anti-emetics,
and anti-inflammatory agents are suitable.
The methods of the invention can be used to treat or prevent cancer in a
subject (e.g., a
human patient) and/or to decrease tumor size. The subject may be diagnosed
with cancer, at risk
for developing cancer, in treatment for cancer, or in post-therapy recovery
from cancer. Further,
the methods can be used to treat or prevent metastases and/or recurrence. The
treatment may
be chemotherapeutic alone, although treatment in combination with a surgical
procedure to
remove or reduce the size of a tumor, radiation therapy, and/or ablation
therapy is also
envisioned.
Types of cancers that can be treated according to the present methods include,
for
example, breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal
cancer, colorectal
cancer, ovarian cancer, endometrial cancer, skin cancer (e.g., melanoma),
prostate cancer, brain
cancer, head and neck cancer, liver cancer, kidney cancer, bladder cancer,
gastric cancer,
gastrointestinal cancer, cancer of the blood (e.g., leukemia), cancer of the
lymphatic system,
thyroid cancer, bone cancer (e.g., osteosarconna), and fibrosarcoma.
8
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
Kits
The invention also provides kits that include a container with eribulin (or a
pharmaceutically acceptable salt thereof, such as eribulin mesylate) and/or a
container with
. lenvatinib (or a pharmaceutically acceptable salt thereof, such as
lenvatinib mesylate). The drugs
in such kits can be provided in amounts sufficient to treat cancer in a
patient in need thereof (e.g.,
amounts sufficient for a single administration or for multiple
administrations). The kits may thus
include multiple containers that each include effective amounts of single-dose
eribulin (or a
pharmaceutically acceptable salt thereof, such as eribulin mesylate) and/or
lenvatinib (or a
pharmaceutically acceptable salt thereof, such as lenvatinib mesylate)
pharmaceutical
composition(s). Optionally, instruments, devices, and/or diluents necessary
for administering the
pharmaceutical composition(s) may also be included in the kits. Furthermore,
the kits may
include additional components, such as instructions or administration
schedules, for treating a
patient with cancer with the drugs.
The present invention is illustrated by the following examples, which are in
no way
intended to be limiting of the invention.
EXAMPLES
Example 1
Effect of E7389 in combination with E7080 in A375 human malignant melanoma
xenografts in
mice
Summary
Antitumor activity of intravenous E7389 (eribulin mesylate) in combination
with oral
E7080 (lenvatinib mesylate) was examined in a preclinical model with
subcutaneous A375 human
malignant melanoma xenografts in female athymic mice. E7389 was administered
at 0.05, 0.2, or
3.0 mg/kg (maximum tolerable dose [MTD]) alone, or was co-administered with 15
mg/kg E7080
(MTD). The combination of E7389 and E7080 generated tumor regression, while
each single
agent resulted in tumor growth delay. Administration of 3.0 mg/kg E7389 on a
once per week for
two weeks (Q7Dx2) schedule in combination with 15 mg/kg E7080 daily dosing for
14 days
(Q1Dx14) resulted in additional body weight loss in animals. However, body
weight recovered
upon completion of drug treatment.
Methods
Preparation of Test Compound Dosing Formulations
E7080 was dissolved in WFI at a concentration of 1.5 mg/mL. E7080 dosing
solution
was formulated for 7 days. The stock solution was aliquoted and stored at 4 C
until use. 0.5
mg/mL E7389 was diluted with 3% ETOH in saline at concentrations of 0.005,
0.02, and
9
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
0.3 mg/mL. E7389 was freshly formulated for each day of dosing.
Measurement of Antitumor Activity
A375 human malignant melanoma cells were maintained in monolayer cultures in
Dulbecco's Modified Eagle's Medium (DMEM) growth medium supplemented with 10%
Fetal
Bovine Serum and 1% of Penicillin-Streptomycin-Glutamine at 37 C in a 5% CO2
humidified
incubator. On the day of inoculation, cells were harvested by Trypsinization,
washed, and mixed
1:1 (v/v) with ice-cold Phosphate Buffered Saline (PBS)/Matrige1 A375
malignant melanoma
cells (5 x 106 cells per animal) were inoculated subcutaneously near the right
axillary area using a
26-gauge needle in a 0.1 mL volume in 80 female imnnuncompromised mice
(Mouse/Crl:NU-
Foxn1nu; Charles River Laboratories).
The experiment consisted of a vehicle-treated control group, a single agent
drug-treated
group for either E7389 or E7080, and three combination drug-treated groups
(summarized in
Table 1). Each group was composed of six mice for a total of 48 mice on the
first day of
treatment. Forty eight out of 80 mice were selected based on their tumor
volumes, and randomly
divided into eight groups which resulted in approximately 300 mm3 of mean
tumor volume in each
group 17 days after tumor implantation. Following randomization, drug
treatment was initiated.
E7080 was orally administered daily for 14 days (Q1Dx14) at a volume of 0.1 mL
per 10 g body
weight. E7389 (0.05 mg/kg) was intravenously administered daily for 14 days.
In the
combination group, E7389 was administered three hours after oral
administration of E7080.
E7389 at 0.2 or 3.0 mg/kg was administered Q7Dx2 either as a single agent or
in combination
with E7080 (Q1Dx14). The control group was treated with vehicle (WFI for oral
daily dosing
(01Dx14) for 14 days and 3% ETOH in saline for intravenous dosing, on a Q7Dx2
schedule).
The general health of the mice was monitored daily. Tumor volume was
determined by
caliper measurements (mm) using the formula (1 x w2)/2 = mm3, where 1 and w
refer to the larger
and smaller perpendicular dimensions collected at each measurement. Tumor
dimensions and
body weight were recorded twice per week starting the first day of treatment.
Relative body
weight was calculated as follows: Relative body weight = (body weight on day
of
measurement)/(body weight on first day of treatment).
The data generated consisted of group mean body weights at each measurement
and
group mean tumor volumes at each measurement. The mean SEM for tumor volume
and
relative body weight for each experimental group was calculated.
Animals whose tumor measurements reached ..20 mm at the longest axis, or in
which
ulceration occurred, were euthanized prior to study termination. The study was
terminated on day
30.
Table 1: Study Design for Investigation of Antitumor activity of E7389 in
combination with E7080
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
in A375 human malignant melanoma xenografts
Group Treatment No. of animals
A Vehicle (WFI) p.o. Q1Dx14 + 3% ETOH saline i.v. Q7Dx2 6
E7080 15 mg/kg p.o. Q1Dx14 6
E7389 0.2 mg/kg i.v. Q7Dx2 6
E7389 3.0 mg/kg i.v. Q7Dx2 6
E7389 0.05 mg/kg i.v. Q1Dx14 6
E7080 15 mg/kg p.o. Q1Dx14 + E7389 0.2 mg/kg i.v. Q7Dx2 6
E7080 15 mg/kg p.o. Q1Dx14 + E7389 3.0 mg/kg i.v. Q7Dx2 6
H E7080 15 mg/kg p.o. Q1Dx14 + E7389 0.05 mg/kg i.v. Q1Dx14 6
Statistical Analysis
Statistical analysis of the E7389 3.0 mg/kg single agent administration and
combination
with E7080 15 mg/kg groups was performed by a one-way analysis of variance
(ANOVA) followed
by Dunnett's multiple comparison test. A value of P <0.05 was considered
statistically significant.
The statistical analysis was performed using Graphpad prism software (version
5).
Results
Figure 1 shows the effect of E7389 in combination with E7080 in A375 human
malignant
melanoma xenografts in mice. Single agent administration of either E7389 or
E7080 at the
highest dose of 3.0 mg/kg (MTD for E7389) and 15 mg/kg (MID for E7080)
resulted in tumor
growth delay, but not tumor regression. The combination of E7389 with E7080
potentiated the
antitumor activity of E7389 at all doses tested. Tumor growth inhibition was
observed at all
combination groups in a dose-dependent fashion (Figure 1). Administration of
3.0 mg/kg E7389
in combination with E7080 caused additional body weight loss. However,
recovery from body
weight loss was observed upon completion of drug treatment (Figure 2).
E7080 was administered orally once daily for 14 days. E7389 at 0.05 mg/kg was
intravenously administered daily for 14 days. In the combination setting,
E7389 was dosed three
hours after the oral administration of E7080. E7389 at 0.2 or 3.0 mg/kg was
administered at
11
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
Q7Dx2 either as a single agent or in combination. The study was terminated on
30 days after
transplantation. Administration of 3.0 mg/kg (Q7Dx2) and 0.05 mg/kg E7389
(Q1Dx14) combined
with 15 mg/kg E7080 daily administration (Q1Dx14) resulted in tumor regression
in this study.
Conclusions
E7389 alone at 3.0 mg/kg and combination treatment showed strong antitumor
activity in
the A375 human malignant melanoma xenograft model. Body weight loss appeared
reversible as
all animals partially recovered upon completion of drug treatment. E7389
administered at a low
dose on a metronomic schedule (0.05 mg/kg Q1Dx14) combined with 15 mg/kg E7080
daily
dosing (Q1Dx14) resulted in significant tumor regression compared to E7389 3.0
mg/kg single
agent treatment.
Example 2
Treatment of breast cancer in a patient by combination therapy
A patient with breast cancer is treated with a combination of E7389 (eribulin
mesylate)
and E7080 (lenvatinib mesylate) according to the following protocol. E7389 is
administered at 1.4
mg/m2 intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.
E7080 is orally
administered at 24 mg/day on each day of the 21-day cycle of E7389 treatment,
starting on the
same day. The patient is treated for a total of 4-6 cycles, depending upon
factors such as the
occurrence and severity of side effects, as well as clinical effects, as
determined by a medical
professional. Optionally, E7080 treatment continues after the end of the E7389
treatment cycles.
Example 3
Effect of E7389 in combination with E7080 in NCI-HI993 and PC-9 human non-
small cell lung
cancer xenografts in mice
Summaiy
Antitumor activity of intravenous E7389 (eribulin mesylate) in combination
with oral
E7080 (lenvatinib mesylate) was examined in a preclinical model with
subcutaneous NCI-H1993
or PC-9 human non-small cell lung cancer xenografts in female athymic mice.
E7389 was
administered at 1.5 mg/kg alone, or was co-administered with 10 mg/kg E7080.
The combination
of E7389 and E7080 showed significantly strong antitumor activity than that of
each monotherapy.
Methods
Preparation of Test Compound Dosing Formulations
E7080 was dissolved in DW at a concentration of 1.0 mg/mL. 0.5 mg/mL E7389 was
diluted with saline at concentrations of 0.15 mg/mL.
12
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
Measurement of Antitumor Activity
Human non-small cell lung cancer cell lines, NCI-H1993 and PC-9, were
maintained in
monolayer cultures in RPMI-1640 medium supplemented with 10% Fetal Bovine
Serum and 1%
of Penicillin-Streptomycin-Amphotericin at 37 C in a 5% CO2 humidified
incubator. On the day of
inoculation, cells were harvested by Trypsinization, washed, and mixed 1:1
(v/v) with
medium/GelTrex. NCI-H1993 and PC-9 human non-small cell lung cancer cells (10
x 106 cells
per animal) were inoculated subcutaneously near the right axillary area using
a 26-gauge needle
in a 0.1 mL volume in female immuncompromised mice (Mouse: BALB/c Slc nu/nu;
Japan SIC,
Inc.).
The experiment consisted of a no inject control group, a single agent drug-
treated group
for either E7389 (1.5 mg/kg) or E7080 (10 mg/kg), and combination drug-treated
groups. Each
group was composed of five mice. Mice were selected based on their tumor
volumes, and
randomly divided into groups which resulted in approximately 200 mm3 (NCI-
H1993: 191 mm3,
PC-9: 227 mm3) of mean tumor volume in each group 10 days (NCI-H1993) or 8
days (PC-9)
after tumor cells inoculation. Following randomization, drug treatment was
initiated. E7389 (1.5
mg/kg) was intravenously administered weekly for two weeks (Q7Dx2). E7080 was
orally
administered daily for 12 days (Q1Dx12). Both drugs were administered at a
volume of 0.1 mL
per 10 g body weight.
Tumor volume was determined by caliper measurements (mm) using the formula
Tumor volume (mm3) = length (mm) x width2 (mm2) x 1/2
Length: largest diameter of tumor
Width: diameter perpendicular to length
The mean SD for tumor volume for each experimental group was calculated.
Statistical Analysis
Statistical analysis of each single agent administration group and combination
group or
no inject group was performed by a two-way RM-ANOVA test. A value of P < 0.05
was
considered statistically significant. The statistical analysis was performed
using Graphpad prism
software (version 6.02).
Results
Figure 3 shows the effect of E7389 in combination with E7080 in NCI-H1993
(left) or PC-
9 (right) human non-small cell lung cancer xenografts in mice. Single
treatment of E7389 (1.5
mg/kg) or E7080 (10 mg/kg) resulted significant antitumor activity in both
xenograft models. The
combination of E7389 with E7080 significantly potentiated the antitumor
activity than that of each
single treatment in both xenograft models.
13
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
Conclusions
Combination treatment of E7389 and E7080 showed significantly stronger
antitumor
activity than that of each single treatment.
Specific Embodiments
Specific embodiments of the invention are as follows:
[1] A method for treating a subject having or at risk of developing cancer,
the method comprising
administering to the subject (i) eribulin or a pharmaceutically acceptable
salt thereof, and (ii)
lenvatinib or a pharmaceutically acceptable salt thereof.
[2] The method of [1], wherein said subject is a human patient.
[3] The method of [1] or [2], wherein said subject is diagnosed with cancer,
in treatment for
cancer, or in post-therapy recovery from cancer.
[4] The method of any one of [1] to [3], wherein said cancer is a primary
tumor.
[5] The method of any one of [1] to [3], wherein said cancer is a metastasis.
[6] The method of any one of [1] to [5], wherein said cancer is a solid tumor.
[7] The method of any one of [1] to [6], wherein said cancer is selected from
the group consisting
of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer,
colorectal cancer,
ovarian cancer, endometrial cancer, skin cancer (e.g., melanoma), prostate
cancer, brain cancer,
head and neck cancer, liver cancer, kidney cancer, bladder cancer, gastric
cancer,
gastrointestinal cancer, cancer of the blood (e.g., leukemia), cancer of the
lymphatic system,
thyroid cancer, bone cancer (e.g., osteosarcoma), and fibrosarcoma.
[8] The method of any one of [1] to [7], wherein said eribulin or said
pharmaceutically acceptable
salt thereof is eribulin mesylate.
[9] The method of any one of [1] to [8], wherein said lenvatinib or said
pharmaceutically
acceptable salt thereof is lenvatinib nnesylate.
[10] The method of any one of [1] to [9], wherein said eribulin or said
pharmaceutically
acceptable salt thereof is administered by intravenous infusion.
14
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
[11] The method of [10], wherein said intravenous infusion is for about 1 to
about 20 minutes.
[12] The method of [11], wherein said intravenous infusion is for about 2 to
about 5 minutes.
[13] The method of any one of [1] to [12], wherein said eribulin or said
pharmaceutically
acceptable salt thereof is administered in an amount in the range of about 0.1
mg/m2 to about 20
mg/m2.
[14] The method of [13], wherein said eribulin or said pharmaceutically
acceptable salt thereof is
administered in an amount of about 1.4 mg/m2 or 1.1 mg/m2.
[15] The method of any one of [1] to [14], wherein said eribulin or said
pharmaceutically
acceptable salt thereof is administered once on each of days 1 and 8 of a 21-
day cycle.
[16] The method of any one of [1] to [15], wherein said lenvatinib, or said
pharmaceutically
acceptable salt thereof, is administered orally.
[17] The method of any one of [1] to [16], wherein said lenvatinib, or said
pharmaceutically
acceptable salt thereof, is administered in an amount in the range of about
0.1 mg to about 100
mg.
[18] The method of [17], wherein said lenvatinib, or said pharmaceutically
acceptable salt thereof,
is administered in an amount in the range of about 4 mg to about 24 mg.
[19] The method of any one of [1] to [18], wherein said lenvatinib, or said
pharmaceutically
acceptable salt thereof, is administered daily.
[20] The method of any one of [1] to [19], wherein said eribulin or said
pharmaceutically
acceptable salt thereof, and said lenvatinib, or said pharmaceutically
acceptable salt thereof, are
administered substantially simultaneously or sequentially.
[21] The method of any one of [1] to [20], wherein said treating: (i) reduces
the number of cancer
cells; (ii) reduces tumor volume; (iii) increases tumor regression rate; (iv)
reduces or slows cancer
cell infiltration into peripheral organs; (v) reduces or slows tumor
metastasis; (vi) reduces or
inhibits tumor growth; (vii) prevents or delays occurrence and/or recurrence
of the cancer and/or
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
extends disease- or tumor-free survival time; (viii) increases overall
survival time; (ix) reduces the
frequency of treatment; and/or (x) relieves one or more of symptoms associated
with the cancer.
[22] A method for decreasing the size of a tumor in a subject, the method
comprising
administering to the subject (i) eribulin or a pharmaceutically acceptable
salt thereof, and (ii)
lenvatinib or a pharmaceutically acceptable salt thereof.
[23] A kit for use in treating cancer, decreasing tumor size, or inducing or
increasing an immune
response to a tumor in a subject, the kit comprising (i) eribulin or a
pharmaceutically acceptable
salt thereof, and (ii) lenvatinib or a pharmaceutically acceptable salt
thereof.
[24] The kit of [23], wherein said (i) eribulin or said pharmaceutically
acceptable salt thereof, and
said (ii) lenvatinib or said pharmaceutically acceptable salt thereof, are in
dosage form.
[25] Eribulin or a pharmaceutically acceptable salt thereof for use in a
method for treating a
subject having or at risk of developing cancer, characterized in that said
compound is
administered to the subject with lenvatinib or a pharmaceutically acceptable
salt thereof.
[26] The eribulin or the pharmaceutically acceptable salt thereof of [25],
wherein said compound
and said lenvatinib, or said pharmaceutically acceptable salt thereof, are
administered
substantially simultaneously or sequentially.
[27] The eribulin or the pharmaceutically acceptable salt thereof of [25] or
[26], wherein said
compound is eribulin mesylate.
[28] Lenvatinib or a pharmaceutically acceptable salt thereof for use in a
method for treating a
subject having or at risk of developing cancer, characterized in that said
compound is
administered to the subject with eribulin or a pharmaceutically acceptable
salt thereof.
[29] The lenvatinib or the pharmaceutically acceptable salt thereof of [28],
wherein said
compound and said eribulin, or said pharmaceutically acceptable salt thereof,
are administered
substantially simultaneously or sequentially.
[30] The lenvatinib or the pharmaceutically acceptable salt thereof of [28] or
[29], wherein said
compound is lenvatinib mesylate.
16
CA 02915005 2015-12-10
WO 2014/208774
PCT/JP2014/067723
[31] A pharmaceutical composition for treating a subject having or at risk of
developing cancer
comprising eribulin or a pharmaceutically acceptable salt thereof,
characterized in that said
pharmaceutical composition is administered to a subject with lenvatinib or a
pharmaceutically
acceptable salt thereof.
[32] A pharmaceutical composition for treating a subject having or at risk of
developing cancer
comprising lenvatinib or a pharmaceutically acceptable salt thereof,
characterized in that said
pharmaceutical composition is administered to a subject with eribulin or a
pharmaceutically
acceptable salt thereof.
[33] The pharmaceutical composition of [31] or [32], wherein said eribulin or
said
pharmaceutically acceptable salt thereof, and said lenvatinib, or said
pharmaceutically acceptable
salt thereof, are administered substantially simultaneously or sequentially.
[34] The pharmaceutical composition of any one of [31] to [33], wherein said
eribulin or said
pharmaceutically acceptable salt thereof is eribulin mesylate.
[35] The pharmaceutical composition of any one of [31] to [33], wherein said
lenvatinib or said
pharmaceutically acceptable salt thereof is lenvatinib mesylate.
[36]. Use of (i) eribulin or a pharmaceutically acceptable salt thereof, and
(ii) lenvatinib or a
pharmaceutically acceptable salt thereof, in the treatment of a subject having
or at risk of
developing cancer, or for decreasing the size of a tumor in a subject.
[37]. Use of (i) eribulin or a pharmaceutically acceptable salt thereof, and
(ii) lenvatinib or a
pharmaceutically acceptable salt thereof, in the preparation of a medicament
for use in the
treatment of a subject having or at risk of developing cancer, or for
decreasing the size of a tumor
in a subject.
The various embodiments noted above with respect to items [2] to [21]
(methods) are applicable
to items [22] (method), [36] (use), and [37] (use).
Other Embodiments
While the invention has been described in connection with specific embodiments
thereof, it will
be understood that it is capable of further modifications and this application
is intended to cover any
variations, uses, or adaptations of the invention following, in general, the
principles of the invention
and including such departures from the present disclosure that come within
known or customary
17
practice within the art to which the invention pertains and may be applied to
the essential features
hereinbefore set forth.
Use of singular forms herein, such as "a" and "the," does not exclude
indication of the
corresponding plural form, unless the context indicates to the contrary.
Similarly, use of plural terms
does not exclude indication of a corresponding singular form. Other
embodiments are within the
scope of the following claims.
18
Date Recue/Date Received 2020-10-09
